CONCLUSIONS Despite similar 52-week glycemic efficacy, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in
type 2 diabetes inadequately controlled with metformin. Long-term studies are required to further evaluate genital and urinary
tract infections with SGLT2 inhibitors.

Metformin is recommended as the initial oral antidiabetic drug (OAD) therapy for patients with type 2 diabetes (1–5), but the progressive nature of type 2 diabetes often requires treatment intensification to maintain glycemic control (6). A sulfonylurea or insulin is commonly added to metformin as a second step (1–5). Although initially effective, sulfonylurea treatment is associated with poor glycemic durability (6), weight gain, and hypoglycemia (7,8).

Dapagliflozin is the first in a novel class of glucose-lowering medications, the selective sodium-glucose cotransporter 2
(SGLT2) inhibitors (9). These agents reduce glucose reabsorption from the proximal tubule of the kidney, leading to increased urinary glucose excretion
with resulting net caloric loss (10). This effect depends on baseline glycemic control and the renal filtration rate but is independent of insulin. Consequently,
reduction in plasma glucose with dapagliflozin reduces the glucose load filtered by the kidney and limits further glucose
excretion, suggesting that dapagliflozin may possess a low intrinsic propensity for hypoglycemia (11). Dapagliflozin might thus provide an alternative to existing add-on therapies by improving glycemic control without associated
weight gain or hypoglycemic risk.

Recent placebo-controlled clinical trials of 24-weeks’ duration have shown promise for dapagliflozin as monotherapy in patients
with type 2 diabetes (12) and as add-on therapy in patients inadequately controlled with metformin (13), but longer-term head-to-head trials comparing dapagliflozin with established therapies are required. The current study
directly tested the efficacy, safety, and tolerability of dapagliflozin against glipizide during a treatment period of 52
weeks in patients with type 2 diabetes inadequately controlled by metformin monotherapy.

RESEARCH DESIGN AND METHODS

Study design

This was a 52-week randomized, double-blind, parallel-group, active-controlled, phase III, noninferiority trial with a 156-week
extension period conducted from 31 March 2008 and ongoing at 95 sites in 10 countries: Argentina, 17 centers; France, 7; Germany,
16; U.K., 12; Italy, 3; Mexico, 4; the Netherlands, 10; South Africa, 10; Spain, 6; and Sweden, 10. Patient disposition is
shown in Supplementary Fig. A1. The study complied with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice
Guidelines, was approved by institutional review boards and independent ethics committees for the participating centers, and
is registered with ClinicalTrials.gov (NCT00660907). All participants provided informed consent before entering the study. Data from the 52-week double-blind treatment period
are presented here.

Inclusion criteria

This study enrolled men and women aged ≥18 years with inadequately controlled type 2 diabetes (HbA1c >6.5 and ≤10%) while receiving metformin or metformin and one other OAD administered up to half-maximal dose for at least
8 weeks before enrollment. A maximum of 25% of randomized patients had a baseline HbA1c <7%. Further criteria included a fasting plasma glucose (FPG) ≤15 mmol/L and C-peptide concentration of ≥0.33 nmol/L. Exclusion
criteria are listed in the Supplementary Data.

Treatments and interventions

Eligible patients receiving metformin monotherapy at a stable dose of <1,500 mg/day or at a variable dose, or combined with
another OAD, entered an 8-week stabilization period during which other OADs were discontinued and the metformin dose was stabilized
to 1,500–2,500 mg/day in all patients. Patients who were already receiving a stable dose of metformin monotherapy (1,500–2,500
mg/day) for at least 8 weeks before enrollment skipped the dose-stabilization period (Supplementary Table A1). Once patients were stabilized, no further changes in the metformin dose were allowed. All patients received dietary and
lifestyle advice commencing from the start of the dose-stabilization period.

After a 2-week, single-blind, placebo lead-in period, patients were randomized in a 1:1 ratio to receive double-blind treatment
with dapagliflozin or glipizide. All patients commenced treatment at dosage level 1, which was dapagliflozin at 2.5 mg or
glipizide at 5 mg. During an 18-week period and at 21-day intervals, patients were up-titrated to the next dosage level if
FPG was ≥6.1 mmol/L. Level 2 was dapagliflozin at 5 mg or glipizide at 10 mg, and level 3 was dapagliflozin at 10 mg or glipizide
at 20 mg. Up-titration continued until the maximum tolerable dose level was reached. A 20-mg limit for glipizide was chosen
because the glycemic benefits of sulfonylureas are virtually complete at half-maximal doses, and higher doses are generally
not recommended (2).

After the 18-week titration period, patients entered a 34-week maintenance period, during which no further up-titration was
allowed. However, patients could be down-titrated to the preceding level or potentially down to level 0 (placebo for both
arms) in the event of recurrent hypoglycemia.

Patients with inadequate glycemic control during the 52-week double-blind treatment period were discontinued according to
time-specific criteria. After having received a maximum titrated or tolerated dose for at least 2 weeks, patients were discontinued
if their FPG was 1) >15 mmol/L at weeks 3, 6, or 9; 2) >13.3 mmol/L at weeks 12, 15, or 18; 3) >12.2 mmol/L at weeks 26 or 34; or 4) >11.1 mmol/L at week 42. Because metformin therapy is contraindicated with renal impairment, patients were also discontinued
at any point in the study if the calculated creatinine clearance using the Cockcroft-Gault equation (14) was <60 mL/min.

Allocation concealment and blinding

Patients were randomized sequentially at study level according to a predefined computer-generated randomization scheme provided
by AstraZeneca. Allocation of study treatments was performed via an Interactive Web Response System in balanced block sizes
of 4 to ensure approximate balance among treatment groups. Blinding of patients and investigators to study treatment was achieved
using a double-dummy technique. Metformin was administered as an open-label treatment throughout the study.

End points and safety assessments

The predefined primary end point was absolute change in HbA1c from baseline to week 52. Key secondary end points were 1) absolute change in total body weight (TBW) from baseline to week 52; 2) proportion of patients reporting at least one episode of hypoglycemia (“major,” “minor,” or “other,” episode) during the
52-week double-blind treatment period; and 3) the proportion of patients achieving a TBW decrease ≥5% from baseline to week 52. Major hypoglycemia was defined as a symptomatic
episode requiring external assistance due to severely impaired consciousness or behavior, with capillary or plasma glucose
levels of 54 mg/dL (<3.0 mmol/L) and recovery after glucose or glucagon administration. Minor hypoglycemia was defined as
a symptomatic episode with capillary or plasma glucose levels of 63 mg/dL (<3.5 mmol/L), irrespective of the need for external
assistance, or an asymptomatic episode with capillary or plasma glucose levels of 63 mg/dL (<3.5 mmol/L) that did not qualify
as a major episode. Other hypoglycemia was defined as an episode with symptoms suggestive of hypoglycemia but without measurement
confirmation.

A number of exploratory end points were assessed, including change from baseline to week 52 for body weight in patients with
a baseline BMI ≥30 kg/m2 and in those with baseline BMI ≥27 kg/m2, waist circumference, change in HbA1c in patients with an HbA1c of ≥7% at baseline, and FPG. The proportions of patients with HbA1c <7% at week 52 in patients with baseline HbA1c ≥7% and proportions of patients with HbA1c ≤6.5% at week 52 were also assessed. Absolute changes from baseline to week 52 for seated systolic and diastolic blood pressure,
and percent changes from baseline to week 52 for total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and free
fatty acids were assessed.

Safety and tolerability was assessed by collating data on adverse events (AEs) using the Medical Dictionary for Regulatory
Activities (MedDRA version 12.1), hypoglycemic events, laboratory tests, calculated creatinine clearance, urinary glucose/creatinine
ratio, electrocardiographic and physical examinations, and vital signs. In addition, patients were actively questioned at
each study visit to assess signs, symptoms, and reports suggestive of genital infections and urinary tract infections (UTIs).
These responses, and those obtained spontaneously, were categorized in the database using a predefined list of MedDRA terms
suggestive of genital infections and UTIs.

Statistical analysis

A hierarchic closed-testing procedure was used to control the type I error rate across the primary and key secondary end points
at the 0.05 level (two-sided). Thus, if noninferiority was established for the primary end point at a one-sided 0.025 significance
level, then key secondary end point testing for superiority could proceed in the sequence described previously. If the first
key secondary end point was significant at a two-sided 0.05 significance level, then the second secondary end point could
be evaluated, and so forth.

The primary and continuous key secondary and exploratory end points were evaluated using ANCOVA, with treatment as the fixed
effect and baseline value as the covariate, to derive a least squares estimate of the treatment difference in mean change
with corresponding two-sided 95% CI. Proportions were analyzed using logistic regression with adjustment for baseline values
as described by Zhang et al. (15). Statistical noninferiority of dapagliflozin versus glipizide was established if the upper limit of the 95% CI for the treatment
difference in mean HbA1c change from baseline to week 52 was <0.35% (noninferiority margin). For graphic presentation of HbA1c and TBW over the 52-week treatment period, the change from baseline (last observation carried forward [LOCF]) was analyzed
at each interval using ANCOVA with treatment as the fixed effect and baseline value as the covariate. The Kaplan-Meier method
was used to analyze time to onset of patient discontinuation because of poor glycemic control.

Two analysis sets were defined: the safety analysis set, consisting of all patients who received one or more doses of the
investigational product, and the full analysis set, consisting of all randomized patients who received one or more doses of
the investigational product and who had a nonmissing baseline and one or more postbaseline efficacy value for one or more
efficacy variable. Primary, key secondary, and exploratory end points were analyzed using the full analysis set. Missing values
at week 52 were replaced using the LOCF method.

Prespecified safety analyses, including events suggestive of genital infection and UTI, were performed using descriptive statistics
for the safety analysis set. A post hoc exploratory analysis of risk differences for the proportions of patients reporting
events suggestive of genital infections and of UTIs were performed using Fisher exact tests. Sample size calculations are
available in the Supplementary Data.

RESULTS

Patients

The full analysis set comprised 801 patients (dapagliflozin: n = 400; glipizide: n = 401) and the safety analysis set, 814 patients (dapagliflozin: n = 406; glipizide: n = 408). Overall, 77.9% of randomized patients completed the study. The commonest reasons for discontinuation were withdrawal
of consent, AEs, and no longer meeting study criteria (Supplementary Fig. A1). Efficacy analyses used LOCF and the full analysis set, which included 98.2% of randomized patients; therefore, almost all
of the discontinued patients were included in these analyses. Demographic and baseline characteristics were balanced across
treatment groups (Supplementary Table A2).

At the end of the titration period, 353 patients (86.9%) randomized to receive dapagliflozin were receiving the maximum dose
of 10 mg, whereas 296 patients (72.5%) randomized to receive glipizide were receiving the maximum dose of 20 mg, resulting
in mean doses of 9.2 mg for dapagliflozin and 16.4 mg for glipizide (Supplementary Table A3). During the titration period, seven patients receiving glipizide versus none receiving dapagliflozin were down-titrated
to receive no study treatment. Overall, 2.7% of patients receiving dapagliflozin versus 15.9% of those receiving glipizide
were down-titrated during the titration or maintenance periods.

Primary end point

The HbA1c adjusted mean change from baseline at week 52 for dapagliflozin was −0.52 (95% CI −0.60 to −0.44) vs. −0.52 (−0.60 to −0.44)
for glipizide; hence, the dapagliflozin HbA1c mean difference from glipizide at week 52 was 0.00 (−0.11 to 0.11). Thus, HbA1c change with dapagliflozin was statistically noninferior to that with glipizide at week 52.

Although the initial drop in HbA1c during the titration period with glipizide was greater than that observed with dapagliflozin, efficacy for glipizide waned
during the maintenance period but remained stable for dapagliflozin. This resulted in equivalent efficacy at week 52 (Fig. 1A). During the maintenance period, 5.1% of patients in the glipizide group were down-titrated versus 0.5% in the dapagliflozin
group (Supplementary Table A3).

Effect of treatments with dapagliflozin (DAPA) and glipizide (GLIP) with metformin (MET) on hypoglycemia, reduction in body
weight, and time to study discontinuation due to lack of glycemic control at 52 weeks. A: Proportion of patients with at least one episode of hypoglycemia at 52 weeks. *Difference vs. GLIP + MET, −37.2% (95% CI
of difference −42.3 to −21.2; P < 0.0001). B: Proportion of patients with ≥5% reduction in body weight at 52 weeks. †Difference vs. GLIP + MET, 30.8% (95% CI of difference
26.0–35.7; P < 0.0001). Data are adjusted proportions and 95% CI according to the methodology of Zhang et al. (15) using the full analysis set and LOCF values. C: Time to study discontinuation due to lack of glycemic control. Symbols represent censored observations. Week is not the
scheduled visit week but the actual number of days from the first dose of double-blind study medication divided by 7. Number
of patients at risk is the number of patients at risk at the beginning of the period.

The adjusted proportion of patients experiencing at least one hypoglycemic episode by week 52 was more than 10-fold lower
with dapagliflozin than with glipizide (Fig. 2A).

The proportion of patients discontinuing due to inadequate glycemic control by week 52 was 0.2% in the dapagliflozin group
versus 3.6% in glipizide group (difference −3.6%; 95% CI −5.3 to −1.5). Time to discontinuation was also prolonged with dapagliflozin
versus glipizide (Fig. 2C).

Exploratory end points

Dapagliflozin reduced seated systolic and diastolic blood pressure, and increased HDL cholesterol (Supplementary Fig. A2). Dapagliflozin reduced body weight in patients with BMI of >27 or >30 kg/m2 and produced glycemic changes equivalent to glipizide, as expected from the noninferior HbA1c result, with the exception of the proportion of patients with HbA1c ≤6.5% at week 52, which favored glipizide (Supplementary Table A4).

Safety and tolerability

Overall AEs.

AEs and serious AEs (SAEs) leading to study discontinuation were balanced across treatment groups (Table 1). SAEs considered related to study treatments were reported in six patients in the dapagliflozin group (complex ventricular
arrhythmia, decreased calculated creatinine clearance, epigastric pain, prostate cancer, pulmonary embolism, and worsening
of coronary artery disease) and in four patients in the glipizide group (hypoglycemia in three and pyelonephritis in one).
No deaths were reported in patients receiving dapagliflozin. Three deaths were reported in the group receiving glipizide,
comprising mesenteric infarction, sudden death at home without autopsy, and acute myocardial infarction.

Overall summary of numbers of patients with an AE, numbers of AEs with frequency ≥3% in any group, and numbers of patients
with AEs of special interest during the 52-week double-blind treatment period using the safety analysis set

AEs led to study discontinuation in 37 patients receiving dapagliflozin (9.1%) versus 24 receiving glipizide (5.9%), which
was mainly accounted for by an excess of patients who were withdrawn because of decreased calculated creatinine clearance
with dapagliflozin (n = 13) versus glipizide (n = 6; Table 1). Creatinine clearance was calculated using the Cockcroft-Gault equation (14), with current body weight values at all visits. A post hoc estimation using baseline weight at each study visit showed no
change in mean calculated creatinine clearance (Supplementary Table A5). One patient receiving dapagliflozin developed acute hepatitis and was later diagnosed with drug-induced acute hepatitis
as well as probable autoimmune hepatitis. This patient’s liver function test values decreased 10 days after suspension of
dapagliflozin and normalized 6 months later in response to immunosuppressive treatment.

Prespecified safety analyses of special interest.

Fewer hypoglycemic events were reported in patients treated with dapagliflozin compared with glipizide (Table 1), and results were comparable with the efficacy analysis of adjusted proportions of patients experiencing hypoglycemia (Fig. 2A). No patients discontinued dapagliflozin treatment as a result of a hypoglycemic event compared with six patients receiving
glipizide. Three patients taking glipizide, but none taking dapagliflozin, reported major hypoglycemic episodes (symptomatic
patients requiring external assistance and with a plasma glucose <3.0 mmol/L).

Higher proportions of patients receiving dapagliflozin reported events suggestive of genital infections or lower UTIs compared
with glipizide. About half of the genital events were recurrent, whereas most of the lower UTIs were single episodes. Except
for three patients, all events were reported as mild or moderate in intensity. Not all of these events could be confirmed
by microbiologic culture, but they nevertheless responded to routine management and rarely led to study discontinuation (Table 1). Two cases of pyelonephritis were reported in the glipizide group, whereas none were reported in the dapagliflozin group
(Table 1).

One report of renal failure (creatinine clearance 106, 95, and 52 mL/min on day −22, 1, and 43, respectively) was considered
related to dapagliflozin and resulted in treatment discontinuation. Although this AE was assessed as mild in intensity, nonserious
by the investigators, and no treatment was administered, no end date for the AE was documented.

Six patients receiving dapagliflozin and three receiving glipizide experienced AEs of hypotension, dehydration, or hypovolemia
(Table 1). None were assessed as serious by the investigators, and no patient discontinued treatment as a consequence.

Laboratory values and vital signs.

Dapagliflozin dramatically increased urinary glucose excretion and the urinary glucose/creatinine ratio (Supplementary Table A5), as expected from its mechanism of action. Dapagliflozin-induced glucose excretion remained elevated and constant from week
12 to 52, showing no sign of diminished activity during this period (Supplementary Fig. A3). Changes from baseline at week 52 with dapagliflozin treatment included increased mean values for hematocrit, blood urea
nitrogen, magnesium, and phosphorus, and decreased mean values for aspartate aminotransferase, alanine aminotransferase, and
serum uric acid. No changes in bilirubin, heart rate, or in the proportions of patients experiencing orthostatic hypotension
were noted (Supplementary Table A5).

CONCLUSIONS

In the context of a dose-titration scheme designed to optimize efficacy and minimize hypoglycemic episodes with glipizide,
this head-to-head comparison study demonstrated that the novel SGLT2 inhibitor dapagliflozin produced a long-term HbA1c mean reduction at 52 weeks that was numerically identical and statistically noninferior to the sulfonylurea glipizide in
patients poorly controlled with metformin monotherapy. This comparable long-term efficacy of dapagliflozin with a sulfonylurea,
considered potent glucose-lowering agents (2), was achieved with >10-fold fewer hypoglycemic episodes along with sustained weight loss. In contrast, weight increased
and hypoglycemic episodes were more frequent with glipizide.

The pattern of HbA1c change over time was substantially different between dapagliflozin and glipizide treatment (Fig. 1A). The pattern with glipizide—rapid initial response, followed by gradual increase—is typical of that observed with sulfonylureas
(6,16). In contrast, dapagliflozin response was initially smaller during titration but thereafter was sustained during the maintenance
period such that it was identical to glipizide response at 52 weeks. It is interesting to speculate whether the durability
of HbA1c control with dapagliflozin will outlast that of glipizide during longer-term follow-up of these patients. In this population
with a relatively low baseline mean HbA1c (∼7.7%), clinically meaningful reductions of >0.5% were achieved by both agents. A higher baseline HbA1c, as observed in other clinical efficacy studies of antidiabetic agents, generally predicts larger drops in response to treatment,
whichever agent is tested (17,18).

Weight loss with dapagliflozin was progressive during the first 6 months and stabilized during the latter half of the study.
This may have resulted from glucosuria-induced fat loss, fluid loss associated with osmotic diuresis, or a combination of
both. Studies of body composition are underway to assess the relative contributions of fat and fluid loss to the changes in
TBW observed with dapagliflozin.

Dapagliflozin reduced blood pressure. The mechanism for this effect is unclear but may involve osmotic diuresis or sodium
loss. Although modest rises in hematocrit and blood urea nitrogen occurred, no meaningful changes were noted in electrolytes,
serum creatinine, heart rate, or proportions of patients experiencing orthostatic hypotension to indicate dehydration. The
estimated glomerular filtration rate and concentrations of cystatin-C did not show meaningful changes. In addition, AEs of
renal impairment or failure—excluding those of decrease in creatinine clearance calculated using current body weight values
at each study visit—were not over-represented with dapagliflozin. Taken together, these data suggest that dapagliflozin treatment
was not associated with clinically relevant dehydration or impairment in kidney function.

Patients with type 2 diabetes are at higher risk of fungal genital infections and UTIs compared with the general population
(19). Dapagliflozin-treated patients, especially women, reported an increase in events suggestive of genital infections and lower
UTIs compared with glipizide-treated patients. For conservative pharmacovigilance purposes with this first-in-class agent,
events suggestive of genital infection and UTI were reported spontaneously and in response to questions proactively posed
to patients that were related to the signs and symptoms of these infections. Not all of these suggestive events could be confirmed
as infections (Table 1). Variable reports of these events have been noted in previous studies with dapagliflozin (13,18,20,21); hence, further analyses using pooled data are required to better evaluate potential risk factors for genital and UTIs with
SGLT2 inhibitors such as dapagliflozin.

In conclusion, this head-to-head comparison of dapagliflozin versus glipizide added to metformin in type 2 diabetic patients
inadequately controlled with metformin monotherapy demonstrated similar glycemic efficacy at 52 weeks but markedly divergent
effects on weight and hypoglycemia. Whereas glipizide treatment led to weight gain and more hypoglycemic episodes, dapagliflozin
produced significant weight loss and significantly fewer hypoglycemic episodes. Dapagliflozin treatment was generally safe
and well tolerated, but events suggestive of genital and lower UTIs were observed more frequently in this study. Dapagliflozin
is a potential valuable alternative to sulfonylureas as add-on therapy when metformin monotherapy fails to maintain adequate
glycemic control.

Acknowledgments

This study was supported by AstraZeneca and Bristol-Myers Squibb. M.A.N. has been a member of advisory boards or has consulted
with AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, Hoffman-La Roche, Menarini/Berlin-Chemie, Merck
Sharp & Dohme, Novo Nordisk, and Versatis. He has received grant support from Eli Lilly & Co., Menarini/Berlin-Chemie, Merck
Sharp & Dohme, Novartis Pharmaceuticals, and Ypsomed. He has served on the speakers’ bureaus of AstraZeneca, Boehringer Ingelheim,
Eli Lilly & Co., Hoffman-La Roche, Menarini/Berlin-Chemie, Merck Sharp & Dohme, and Novo Nordisk. S.D.P. has been a member
of advisory boards with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly & Co., GlaxoSmithKline, Merck Sharp
& Dohme, Novartis Pharmaceuticals, Novo Nordisk, Roche Pharmaceuticals, sanofi-aventis, and Takeda Pharmaceuticals. He has
received grant support from Merck Sharp & Dohme, sanofi-aventis, and Takeda Pharmaceuticals. He has served on the speakers’
bureaus of GlaxoSmithKline and sanofi-aventis. J.J.M. has received speaker or advisory board fees from AstraZeneca, Menarini/Berlin-Chemie,
Bristol-Myers Squibb, Eli Lilly & Co., Merck Sharp & Dohme, Novartis Pharmaceuticals, Novo Nordisk, Roche Pharmaceuticals,
and sanofi-aventis. He has received research support from Eli Lilly & Co., Merck Sharp & Dohme, Novartis Pharmaceuticals,
Novo Nordisk, and sanofi-aventis. K.R. and S.J.P. are full-time employees of AstraZeneca Pharmaceuticals. M.E. is an employee
of ClinResearch, which is contracted to support data analysis for AstraZeneca. No other potential conflicts of interest relevant
to this article were reported.

M.A.N., S.D.P., and S.D.-G. acquired data, analyzed and interpreted data, and wrote and revised the article. J.J.M. and S.J.P.
contributed to the study concept and design, analyzed and interpreted data, and wrote and revised the article. K.R. supervised
the study, analyzed and interpreted data, and wrote and revised the article. M.E. contributed to the study concept and design,
contributed to statistical verification of data, analyzed and interpreted data, and wrote and revised the article.

Parts of this study were presented in abstract form at the 46th Annual Meeting of the European Association for the Study of
Diabetes, Stockholm, Sweden, 20–24 September 2010, and at the 71st Scientific Sessions of the American Diabetes Association,
San Diego, California, 24–28 June 2011.

; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy:
a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care2009;32:193–203pmid:18945920

. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus
statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care2006;29:1963–1972pmid:16873813

. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised,
double-blind, placebo-controlled trial. Lancet2010;375:2223–2233pmid:20609968